Mirtazapine: uses, appearance and warnings

Mirtazapine tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)] . Mirtazapine tablets are indicated for the treatment of major depressive disorder (MDD) in adults. (1)

Mirtazapine Tablets, USP are supplied as: 7.5 mg tablets: Yellow colored, round, biconvex film-coated tablets debossed with “886” on one side and “N” on the other side, free from physical defects 15 mg tablets: Yellow colored, oblong, biconvex film-coated tablets, functionally scored on one side and debossed with “N 887” on the other side, free from physical defects 30 mg tablets: Brown colored, oblong, biconvex film-coated tablets, functionally scored on one side and debossed with “N 888” on the other side, free from physical defects 45 mg tablets: White to off white colored, oblong, biconvex film-coated tablets debossed with “N 889” on one side and plain on the other side, free from physical defects Tablets : 7.5 mg unscored, 15 mg functionally scored, 30 mg functionally scored and 45 mg unscored. (3)

Mirtazapine Tablets, USP are supplied as: Tablet Strength Tablet Color/Shape Tablet Markings Package Configuration NDC Code 7.5 mg Yellow colored, round, biconvex film-coated tablets Debossed with “886” on one side and “N” on the other side, free from physical defects Bottle / 30 count 70954-830-10 15 mg Yellow colored, oblong, biconvex film-coated tablets Functionally scored on one side and debossed with “N 887” on the other side, free from physical defects Bottle / 30 count 70954-887-10 30 mg Brown colored, oblong, biconvex film-coated tablets Functionally scored on one side and debossed with “N 888” on the other side, free from physical defects Bottle / 30 count 70954-888-10 45 mg White to off white colored, oblong, biconvex film-coated tablets Debossed with “N 889” on one side and plain on the other side, free from physical defects Bottle / 30 count 70954-889-10 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

Mirtazapine tablets are contraindicated in patients: Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)] . With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets . Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see Warnings and Precautions (5.6), Adverse Reactions (6.2)]. Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. (2.4, 4, 7) Known hypersensitivity to mirtazapine or any of the excipients in mirtazapine tablets. (4)

Agranulocytosis : If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with mirtazapine tablets should be discontinued and the patient should be closely monitored. (5.2) Serotonin Syndrome : Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue mirtazapine tablets and initiate supportive treatment. (2.4, 4, 5.3, 7) Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.4) QT Prolongation : Use mirtazapine tablets with caution in patients with risk factors for QT prolongation. (5.5, 7) Drug Reaction with Eosinophilia and System Symptoms (DRESS) : Discontinue mirtazapine tablets if DRESS is suspected. (5.6) Increased Appetite/Weight Gain : Mirtazapine tablets have been associated with increased appetite and weight gain. (5.7) Somnolence : May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. (5.8, 7) Activation of Mania/Hypomania : Screen patients for bipolar disorder prior to initiating treatment. (2.3, 5.9) Seizures : Use with caution in patients with a seizure disorder. (5.10) Elevated Cholesterol/Triglycerides : Has been reported with mirtazapine tablets use. (5.11) Hyponatremia : May occur as a result of treatment with serotonergic antidepressants, including mirtazapine tablets. (5.12) Transaminase Elevations : Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated <18 years old 18–24 years old Increases Compared to Placebo 14 additional patients 5 additional patients 25–64 years old ≥65 years old Decreases Compared to Placebo 1 fewer patient 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing mirtazapine tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with mirtazapine tablets developed agranulocytosis [absolute neutrophil count (ANC) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after mirtazapine tablets were stopped. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with mirtazapine tablets should be discontinued and the patient should be closely monitored. 5.3 Serotonin Syndrome Serotonergic antidepressants, including mirtazapine tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7)] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of mirtazapine tablets with MAOIs is contraindicated. In addition, do not initiate mirtazapine tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. …

The following adverse reactions are described in more detail in other sections of the prescribing information: Hypersensitivity [see Contraindications (4)] Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] Agranulocytosis [see Warnings and Precautions (5.2)] Serotonin Syndrome [see Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)] Angle-Closure Glaucoma [see Warnings and Precautions (5.4)] QT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] Increased Appetite and Weight Gain [see Warnings and Precautions (5.7)] Somnolence [see Warnings and Precautions (5.8)] Activation of Mania or Hypomania [see Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Elevated Cholesterol and Triglycerides [see War …

Table 5 includes clinically important drug interactions with mirtazapine tablets [see Clinical Pharmacology (12.3)]. Table 5: Clinically Important Drug Interactions with Mirtazapine Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of serotonergic drugs, including mirtazapine tablets, and MAOIs increases the risk of serotonin syndrome. Intervention Mirtazapine tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3)]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with mirtazapine tablets increases the risk of serotonin syndrome. …